Recent studies from our laboratory suggest that the kB kinase, IKKb, may promote insulin resistance in obesity and patients with type 2 diabetes. We hypothesize IKKb to be a central, signal integration site that is activated by obesity, free fatty acids and hyperglycemia, and that leads to insulin resistance by directly or indirectly increasing levels of insulin receptor/insulin receptor substrate Ser/Thr phosphorylation. Furthermore, we hypothesize that reduced lKKb activity, as results from inhibiting the enzyme or reducing IKKb levels through targeted gene deletion, confers in vivo protection against the development of insulin resistance. I will test these hypotheses by generating mice that selectively over-express activated IKKb in insulin target tissues, including muscle, fat and liver. In addition to creating the mice, I will carefully characterize their metabolic phenotypes. These studies will determine whether tissue-specific increases in lKKb activity cause whole body insulin resistance and further ask whether lKKb activation in one tissue influences insulin sensitivity in others.